Type-1 diabetes results from autoimmune destruction of the insulin-secreting beta cells within pancreatic islets. Typically it affects children and young adults. Proper management of type 1 diabetes requires frequent glucose monitoring and life-long insulin administration. In conjunction with new strategies to induce immune tolerance, the transplantation of healthy islet and beta cells to replace the lost cells may be a cure for the disease. However, a primary challenge remains—the scarcity of functional, glucose-responsive beta cells.
Researchers have been hopeful that stem cells could provide an unlimited source of functional beta cells. Stepwise differentiation conditions have been proposed that recapitulate developmental signaling and that purportedly differentiate pluripotent stem cells through a definitive endoderm stage all the way into functional pancreatic beta cells (D'Amour, Agulnick et al. 2005; Yasunaga, Tada et al. 2005; Gouon-Evans, Boussemart et al. 2006; Jiang, Shi et al. 2007; Kroon, Martinson et al. 2008; Green, Chen et al. 2011). However, use of stem cells as the starting material for generating pancreatic cells has problems, including lack of availability, potential immunological rejection, and social concerns.
Direct beta-cell reprogramming methods could be faster and more efficient than preparing induced pluripotent stem cells (iPSCs). However, a general approach to converting non-endoderm cells, such as fibroblast cells, across the germ-layer boundary towards an endoderm-beta cell lineage has not yet been developed. Cell types derived from the endoderm lineage, such as acinar cells or hepatocytes, might be easier to reprogram into a beta cell lineage owing to their similarity to beta cells. However, these methods have not been successfully applied to cell-based therapy or in vivo therapy because of the practicality of obtaining useful starting cells. In addition, beta-like cells generated by conventional direct reprogramming are post-mitotic and have very limited regenerative ability. Pancreatic progenitor cells would be a better cell source for transplantation because of their potential for sustained proliferation and proper differentiation. However, successful methods for reliably obtaining clinically useful numbers of pancreatic progenitor cells are not available.